PDE 7 Inhibitors: New Potential Drugs for the Therapy of Spinal Cord Injury

Abstract

BackgroundPrimary traumatic mechanical injury to the spinal cord (SCI) causes the death of a number of neurons that to date can neither be recovered nor regenerated. During the last years our group has been involved in the design, synthesis and evaluation of PDE7 inhibitors as new innovative drugs for several neurological disorders. Our working hypothesis is based on two different facts. Firstly, neuroinflammation is modulated by cAMP levels, thus the key role for phosphodiesterases (PDEs), which hydrolyze cAMP, is undoubtedly demonstrated. On the other hand, PDE7 is expressed simultaneously on leukocytes and on the brain, highlighting the potential crucial role of PDE7 as drug target for neuroinflammation.Methodology/Principal FindingsHere we present two chemically diverse families of PDE7 inhibitors, designed using computational techniques such as virtual screening and neuronal networks. We report their biological profile and their efficacy in an experimental SCI model induced by the application of vascular clips (force of 24 g) to the dura via a four-level T5–T8 laminectomy. We have selected two candidates, namely S14 and VP1.15, as PDE7 inhibitors. These compounds increase cAMP production both in macrophage and neuronal cell lines. Regarding drug-like properties, compounds were able to cross the blood brain barrier using parallel artificial membranes (PAMPA) methodology. SCI in mice resulted in severe trauma characterized by edema, neutrophil infiltration, and production of a range of inflammatory mediators, tissue damage, and apoptosis. Treatment of the mice with S14 and VP1.15, two PDE7 inhibitors, significantly reduced the degree of spinal cord inflammation, tissue injury (histological score), and TNF-α, IL-6, COX-2 and iNOS expression.Conclusions/SignificanceAll these data together led us to propose PDE7 inhibitors, and specifically S14 and VP1.15, as potential drug candidates to be further studied for the treatment of SCI.

Neurological, Functional, and Biomechanical Characteristics After High-Velocity Behind Armor Blunt Trauma of the Spine

“…It has been reported that phosphodiesterase 7 inhibitors significantly reduce the degree of spinal inflammation. 36 Progesterone can promote the regeneration of myelin and neurons. 37 Enhancing Sox11b (a transcription factor) expression was reported to promote the proliferation and neurogenic determination of endogenous neural stem cells after injury.…”

Dual inhibitor of PDE7 and GSK-3 – VP1.15 acts as antipsychotic and cognitive enhancer in C57BL/6J mice

“…VP1.15 was synthesized in the Instituto de Quimica Medica (Madrid, Spain) as described previously (Paterniti et al, 2011;Palomo et al, 2012;Pérez et al, 2012), Damphetamine (2.5 mg/kg and 5 mg/kg; Sigma) and MK-801 maleate salt (0.3 mg/kg, Sigma) were dissolved in 0.9% NaCl and injected intraperitoneally (i.p.) 30 min prior to the experimental session.…”

“…30 min prior to the experimental session. Doses of VP1.15 (3 mg/kg and 7.5 mg/kg), D-amphetamine and MK-801 were chosen based on the literature (Paterniti et al, 2011;Lipina et al, 2011, Lipina andHalene and Siegel, 2008). Doses of D-amphetamine and MK-801 were expressed as salt and doses of VP1.15 were expressed as free-base.…”

“…To date there are no reports yet about behavioural effect of specific PDE7 inhibitors as well as behavioural repertoire of PDE7 genetic mice. In this context, using drug discovery computational model such as virtual screening and neuronal network, a dual inhibitor of PDE7 and GSK-3 e 5-imino-1,2-4-thiaiazoles and quinazolines derivative e VP1.15, that has been recently developed Paterniti et al, 2011;Pérez et al, 2012), offers a unique opportunity to probe its efficacy as potentially novel antipsychotic drug.…”

Theophylline regulates inflammatory and neurotrophic factor signals in functional recovery after C2-hemisection in adult rats

“…Based on the present finding that TNF-α levels are enhanced in injury, we speculate that over time (in chronic injury), enhanced levels of TNF-α may persist and can potentially limit the efficacy of the drug in improving respiratory function. In fact, it has been previously suggested that TNF-α is important in chronic inflammation (Tzeng et al, 1999; Paterniti et al, 2011). Furthermore, a recent clinical study on the efficacy of the drug to improve inspiratory capacity provided mixed results in the beneficial effects of theophylline in improving function in a population of chronic SCI patients (Tzelepis et al, 2008).…”